The biological activities of many pharmaceuticals, fragrances, food additives and agrochemicals are often associated with their absolute molecular configuration. While one enantiomer gives a desired biological function through interactions with natural binding sites, another enantiomer usually does not have the same function and sometimes has deleterious side effects. As such, chemical synthesis of biologically active compounds are usually directed at the desired enantiomerically pure form.
Cyclopropanes are particularly challenging to synthesize enantiomerically pure. Especially for commercial applications, stereoselective cyclopropanations must give good diastereo- and enantioselectivity in high yield and purity at a reasonable cost. One approach that is particularly efficient, is stereoselective catalysis because a small amount of a chiral catalyst can be used to produce a large quantity of the desired chiral cyclopropyl compound. Transition metal catalysts are typically employed to catalyze the reaction between a diazoester and an olefin substrate to form a chiral cyclopropyl product.
Current stereoselective cyclopropanation methods using transition metal catalysis, are nonoptimal for commercialization due to the use of a large excess olefin substrate or diazoester in order to drive the reaction to completion. Miller et al. (Angew. Chem Int. Ed. 2002, 41, 2953-2956) report an isolated ruthenium catalyst formed from a chiral salen ligand and pyridine or phosphine ligands. The stereoselective cyclopropanation method of Miller et al. employs an isolated chiral ruthenium catalyst and five equivalents of the olefin substrate relative to the amount of diazoester employed. In commercial applications, the olefin substrates are often complex and require multi-step syntheses. As a result, using an excess of the olefin substrate not only wastes material, but also increases cost and lowers the throughput of the chemical process. On the other hand, using a large excess of the diazoester to drive the reaction to completion is undesirable due to safety concerns on large scale. Furthermore, use of excess reagents can lead to increased impurities and purification difficulties. Finally, the use of an isolated chiral catalyst can be undesirable in commercial applications because of the increased number of steps in a chemical process, increasing cycle time, as well as safety issues associated with handling transition metal catalysts. What is needed, are efficient transition metal catalyzed stereoselective cyclopropanation methods employing mild and safe conditions.